The role of NOTCH1 signaling in T-ALL.
The role of NOTCH1 signaling in T-ALL.
复制标题
DOI：
10.1182/asheducation-2009.1.353
复制
发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Ferrando, Adolfo A
中科院分区：
文献类型：
--
作者：
Ferrando, Adolfo A
在超过50%的t细胞急性淋巴细胞白血病（T-ALL）中发现NOTCH1的激活突变，这引起了人们对阐明致癌NOTCH的下游转化机制和NOTCH信号通路在该疾病中的靶向作用的重大兴趣。小分子γ -分泌酶抑制剂（GSIs）可阻断T-ALL淋巴细胞中的NOTCH1信号，但由于胃肠道毒性的发展及其对人T-ALL的弱抗白血病作用，GSIs的临床发展一直受到阻碍。然而，随着对介导gsi在白血病细胞和肠上皮中的作用的分子机制的理解的提高，旨在优化抗notch1治疗T-ALL的新治疗策略，包括与分子靶向药物和糖皮质激素联合治疗，已经开始出现。本文就NOTCH1诱导T-ALL细胞转化的分子基础、致癌NOTCH1的作用机制及NOTCH1突变在T-ALL中的临床意义进行综述。
The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.